title: Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype.
abstract: OBJECTIVE
  Obese Alms1 mutant (foz/foz) NOD.B10 mice develop diabetes and fibrotic NASH when fed high-fat(HF) diet. To establish whether diabetes or obesity is more closely associated with NASH fibrosis, we compared diabetic foz/foz C57BL6/J with non-diabetic foz/foz BALB/c mice. We also determined hepatic cytokines, growth factors and related profibrotic pathways.
  
  
  METHODS
  Male and female foz/foz BALB/c and C57BL6/J mice were fed HF or chow for 24 weeks before determining metabolic indices, liver injury, cytokines, growth factors, pathology/fibrosis and matrix deposition pathways.
  
  
  RESULTS
  All foz/foz mice were obese. Hepatomegaly, hyperinsulinemia, hyperglycaemia and hypoadiponectinaemia occurred only in foz/foz C57BL6/J mice, whereas foz/foz BALB/c formed more adipose. Serum ALT, steatosis, ballooning, liver inflammation and NAFLD activity score were worse in C57BL6/J mice. In HF-fed mice, fibrosis was severe in foz/foz C57BL6/J, appreciable in WT C57BL6/J, but absent in foz/foz BALB/c mice. Hepatic mRNA expression of TNF-α, IL-12, IL-4, IL-10 was increased (but not IFN-γ, IL-1β, IL-17A), and IL-4:IFN-γ ratio (indicating Th-2 predominance) was higher in HF-fed foz/foz C57BL6/J than BALB/c mice. In livers of HF-fed foz/foz C57BL6/J mice, TGF-β was unaltered but PDGFα and CTGF were increased in association with enhanced α-SMA, CD147and MMP activity.
  
  
  CONCLUSIONS
  In mice with equivalent genetic/dietary obesity, NASH development is linked to strain differences in hyperinsulinaemia and hyperglycaemia inversely related to lipid partitioning between adipose and liver. Diabetes-mediated CTGF-regulation of MMPs as well as cytokines/growth factors (Th-2 cytokine predominant, PDGFα, not TGF-β) mobilized in the resultant hepatic necroinflammatory change may contribute to strain differences in NASH fibrosis.
authors.affiliation: Liver Research Group, Australian National University Medical School at The Canberra Hospital, Garran, ACT, Australia.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Farrell
authors.forename: Auvro R
authors.initials: AR
authors.lastname: Mridha
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: Todor
authors.initials: T
authors.lastname: Arsov
authors.forename: Derrick M
authors.initials: DM
authors.lastname: Van Rooyen
authors.forename: John
authors.initials: J
authors.lastname: Brooling
authors.forename: Tori
authors.initials: T
authors.lastname: Nguyen
authors.forename: Deborah
authors.initials: D
authors.lastname: Heydet
authors.forename: Viviane
authors.initials: V
authors.lastname: Delghingaro-Augusto
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nolan
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Shackel
authors.forename: Susan V
authors.initials: SV
authors.lastname: McLennan
authors.forename: Narci C
authors.initials: NC
authors.lastname: Teoh
authors.forename: Claire Z
authors.initials: CZ
authors.lastname: Larter
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018797:Cell Cycle Proteins; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D005455:Fluorescent Antibody Technique; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000473:pathology; D013045:Species Specificity
chemical_list: C510001:Alms1 protein, mouse; D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020782:Matrix Metalloproteinases
keywords: Non-alcoholic steatohepatitis; cytokines; fibrosis; growth factors; strain difference